tbuckley/cabot-search huggingface dataset:
Wolff-Parkinson-White Syndrome in the Era of Catheter Ablation
Authors: Carlo Pappone, Gabriele Vicedomini, Francesco Manguso, Massimo Saviano, Mario Baldi, Alessia Pappone, Cristiano Ciaccio, Luigi Giannelli, Bogdan Ionescu, Andrea Petretta, Raffaele Vitale, Amarild Cuko, Zarko Calovic, Angelica Fundaliotis, Mario Moscatiello, Luigi Tavazzi, Vincenzo Santinelli
Journal: Circulation (2014)

Background— The management of Wolff-Parkinson-White is based on the distinction between asymptomatic and symptomatic presentations, but evidence is limited in the asymptomatic population. Methods and Results— The Wolff-Parkinson-White registry was an 8-year prospective study of either symptomatic or asymptomatic Wolff-Parkinson-White patients referred to our Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-RFA group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-RFA group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period ( P &lt;0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation ( P &lt;0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P &lt;0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds. Conclusions— The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes.
Contribution of dynamic vascular wall thickening to luminal narrowing during coronary arterial constriction.
Authors: R N MacAlpin
Journal: Circulation (1980)

Available estimates of the ratio of wall thickness to luminal radius of human coronary arteries and certain geometrical assumptions were used to calculate the amounts of vascular smooth muscle shortening required to produce specific changes in luminal diameter for hypothetical "normal" and stenotic arteries. The results indicate that even modest mural thickening due to disease may act as a "lever" in translating physiologic degrees of medial smooth muscle shortening into critical luminal obstructions, providing the diseased segment maintains some pliability. The possibility of acute luminal occlusion occurring at stenotic sites as the result of "normal" vasomotion is illustrated. The appropriate use of the term coronary arterial "spasm" is discussed in light of these observations.
Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in Patients With Advanced Squamous Cell Cancer of the Cervix
Authors: R. Pearcey, M. Brundage, P. Drouin, J. Jeffrey, D. Johnston, H. Lukka, G. MacLean, L. Souhami, G. Stuart, D. Tu
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS: A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease ≥ 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m 2 ) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS: A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P = .33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P = .42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION: This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m 2 to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.
Clinical availability of nonalcoholic fatty liver disease as an early predictor of type 2 diabetes mellitus in korean men: 5-year prospective cohort study
Authors: Sung Keun Park, Mi Hae Seo, Ho Cheol Shin, Jae-Hong Ryoo
Journal: Hepatology (2012)

Abstract There have been several reports about the clinical association between type 2 diabetes mellitus (DM) and nonalcoholic fatty liver disease (NAFLD). However, most of the studies were about the unilateral effects of type 2 DM on NAFLD, and studies on the reverse relation are rare. Thus, this study was designed to investigate the effect of NAFLD on type 2 DM. We conducted a prospective cohort study on 25,232 Korean men without type 2 DM for 5 years. We serially checked the various metabolic factors including fasting glucose and hemoglobin A1c (HbA1c), and monitored the development of type 2 DM. The incidence rate of type 2 DM was compared according to the degree of NAFLD (normal, mild, and moderate to severe), and a Cox proportional hazards model was used to measure the hazard ratios (HRs) of NAFLD on type 2 DM. The incidence rate of type 2 DM increased according to the degree of NAFLD (normal: 7.0%, mild: 9.8%, moderate to severe: 17.8%, P &lt; 0.001). Even after adjusting for other multiple covariates, the HRs (95% confidence interval [CI]) for type 2 DM development was higher in the mild group (1.09; 0.81-1.48) and moderate to severe group (1.73; 1.00-3.01) compared to the normal group, respectively ( P for trend &lt;0.001). Conclusion : The development of type 2 DM is potentially more associated with more progressive NAFLD than a normal or milder state. In addition, NAFLD was an independent risk factor for the future development of type 2 DM. These results suggest the potential availability of NAFLD as an early predictor of type 2 DM.
High Prevalence of Osteonecrosis of the Femoral Head in HIV-Infected Adults
Authors: Kirk D. Miller, Henry Masur, Elizabeth C. Jones, Galen O. Joe, Margaret E. Rick, Grace G. Kelly, JoAnn M. Mican, Shuying Liu, Lynn H. Gerber, William C. Blackwelder, Judith Falloon, Richard T. Davey, Michael A. Polis, Robert E. Walker, H. Clifford Lane, Joseph A. Kovacs
Journal: Annals of Internal Medicine (2002)

Background: Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing. Objective: To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis. Design: Survey and comparison study. Setting: The Clinical Center of the U.S. National Institutes of Health. Participants: 339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999. Measurements: Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state. Results: Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies. Conclusions: Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.
Not just an anti-eosinophil drug: tezepelumab treatment for type 2 asthma and beyond
Authors: Jonathan Corren, Christopher E. Brightling, Louis-Philippe Boulet, Celeste Porsbjerg, Michael E. Wechsler, Andrew Menzies-Gow, Christopher S. Ambrose, Bill Cook, Neil Martin, Joseph Spahn, Jean-Pierre Llanos
Journal: European Respiratory Journal (2023)

<b>Tezepelumab, a biologic therapy for severe asthma, blocks TSLP activity, subsequently downregulating multiple type 2 inflammatory pathways and reducing airway hyperresponsiveness <i>via</i> eosinophil-independent effects</b> https://bit.ly/3XGpaV3
Cellular and Molecular Biology of the Presynaptic Nerve Terminal
Authors: W S Trimble, M Linial, R H Scheller
Journal: Annual Review of Neuroscience (1991)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
How Can Care for Depression Become More Cost-effective?
Authors: Roland Sturm
Journal: JAMA (1995)

<h3>Objective.</h3> —To determine the cost and health effects of changes in the content and quality of care for depressed patients treated in prepaid general medical practices (internal and family medicine) and mental health specialty practices and shifts in the proportion of patients treated in general medicine. <h3>Methods.</h3> —Cost-effectiveness analysis and simulations, which are empirically based on data from the Medical Outcomes Study. <h3>Outcome Measures.</h3> —Change in serious functional limitations, annual treatment costs per patient, and costs per reduction in one functional limitation. <h3>Results.</h3> —More appropriate care for depression (increased counseling, use of appropriate antidepressant medications, or avoidance of regular minor tranquilizer use) improves functioning outcomes. Although this approach increases total costs of care, it also improves the value of care because each dollar spent on care now provides more benefits in terms of health improvements. In contrast with the effects of more appropriate care for depression, the trend away from mental health specialty care and toward general medical provider care under current treatment patterns reduces costs, worsens outcomes, and does not increase the value of health care spending in terms of health improvement per dollar. <h3>Conclusion.</h3> —Quality improvement measures that roughly follow practice guidelines for depression can improve outcomes and the value or cost-effectiveness of care, but at increased treatment costs; shifting patients away from mental health specialists decreases costs but worsens functioning outcomes. The best strategy for making care for depression more cost-effective is through quality improvement, not through changing specialty mix. Yet combining these strategies may achieve better outcomes, lower treatment costs, and better value of care compared with current practice patterns. To realize this potential, however, substantial quality improvement of care for depression is necessary in general medical practice. (<i>JAMA</i>. 1995;273:51-58)
The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes
Authors: Franklin H. Epstein, Valentin Fuster, Lina Badimon, Juan J. Badimon, James H. Chesebro
Journal: New England Journal of Medicine (1992)

The Pathogenesis of Thrombus FormationHaving discussed the participation of thrombus formation in the progression of atherosclerosis and in the acute coronary syndromes (Fig. 2 and 5), we shall now examine the local and systemic factors present at the time of coronary plaque disruption that may influence the degree and duration of thrombus deposition and account for the various pathologic and clinical manifestations (Table 2). The Degree of Plaque Disruption As an initial approach to the understanding of the thrombotic process that follows plaque disruption, Badimon et al. have developed a computer-assisted nuclear-scintigraphic method using an extracorporeal-perfusion system to study . . .
Localization of DNA sequences required for human centromere function through an analysis of rearranged Y chromosomes
Authors: Chris Tyler-Smith, Rebecca J. Oakey, Zoia Larin, Richard B. Fisher, Mark Crocker, Nabeel A. Affara, Malcolm A. Ferguson-Smith, Maximilian Muenke, Orsetta Zuffardi, Mark A. Jobling
Journal: Nature Genetics (1993)
Primary and Acquired Resistance of Colorectal Cancer Cells to Anti-EGFR Antibodies Converge on MEK/ERK Pathway Activation and Can Be Overcome by Combined MEK/EGFR Inhibition
Authors: Teresa Troiani, Stefania Napolitano, Donata Vitagliano, Floriana Morgillo, Anna Capasso, Vincenzo Sforza, Anna Nappi, Davide Ciardiello, Fortunato Ciardiello, Erika Martinelli
Journal: Clinical Cancer Research (2014)

Abstract Purpose: The EGFR-independent activation of the RAS/RAF/MEK/MAPK pathway is one of the resistance mechanisms to cetuximab. Experimental Design: We have evaluated, in vitro and in vivo, the effects of BAY 86-9766, a selective MEK1/2 inhibitor, in a panel of human colorectal cancer cell lines with primary or acquired resistance to cetuximab. Results: Among the colorectal cancer cell lines, five with a KRAS mutation (LOVO, HCT116, HCT15, SW620, and SW480) and one with a BRAF mutation (HT29) were resistant to the antiproliferative effects of cetuximab, whereas two cells (GEO and SW48) were highly sensitive. Treatment with BAY 86-9766 determined dose-dependent growth inhibition in all cancer cells, including two human colorectal cancer cells with acquired resistance to cetuximab (GEO-CR and SW48-CR), with the exception of HCT15 cells. Combined treatment with cetuximab and BAY 86-9766 induced a synergistic antiproliferative and apoptotic effects with blockade in the MAPK and AKT pathway in cells with either primary or acquired resistance to cetuximab. The synergistic antiproliferative effects were confirmed using other two selective MEK1/2 inhibitors, selumetinib and pimasertib, in combination with cetuximab. Moreover, inhibition of MEK expression by siRNA restored cetuximab sensitivity in resistant cells. In nude mice bearing established human HCT15, HCT116, SW48-CR, and GEO-CR xenografts, the combined treatment with cetuximab and BAY 86-9766 caused significant tumor growth inhibition and increased mice survival. Conclusion: These results suggest that activation of MEK is involved in both primary and acquired resistance to cetuximab and the inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance in patients with colorectal cancer. Clin Cancer Res; 20(14); 3775–86. ©2014 AACR.
Diagnosis and Management of Headache
Authors: Matthew S. Robbins
Journal: JAMA (2021)

<h3>Importance</h3> Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide. <h3>Observations</h3> Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT<sub>1B/D</sub>agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene–related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT<sub>1F</sub>agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene–related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo. <h3>Conclusions and Relevance</h3> Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.
KRN951, a Highly Potent Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases, Has Antitumor Activities and Affects Functional Vascular Properties
Authors: Kazuhide Nakamura, Eri Taguchi, Toru Miura, Atsushi Yamamoto, Kazumi Takahashi, Francis Bichat, Nicolas Guilbaud, Kazumasa Hasegawa, Kazuo Kubo, Yasunari Fujiwara, Rika Suzuki, Kinya Kubo, Masabumi Shibuya, Toshiyuki Isae
Journal: Cancer Research (2006)

Abstract Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities. KRN951 potently inhibited VEGF-induced VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited ligand-induced phosphorylation of platelet-derived growth factor receptor-β (PDGFR-β) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively). KRN951 blocked VEGF-dependent, but not VEGF-independent, activation of mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats, KRN951 decreased the microvessel density within tumor xenografts and attenuated VEGFR-2 phosphorylation levels in tumor endothelium. It also displayed antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in tumor vascular hyperpermeability was closely associated with the antitumor activity of KRN951. These findings suggest that KRN951 is a highly potent, p.o. active antiangiogenesis and antitumor agent and that DCE-MRI would be useful in detecting early responses to KRN951 in a clinical setting. KRN951 is currently in phase I clinical development for the treatment of patients with advanced cancer. (Cancer Res 2006; 66(18): 9134-42)
8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes <i>Ogg1</i> Knockout Mice Susceptible to Skin Carcinogenesis
Authors: Makoto Kunisada, Kunihiko Sakumi, Yohei Tominaga, Arief Budiyanto, Masato Ueda, Masamitsu Ichihashi, Yusaku Nakabeppu, Chikako Nishigori
Journal: Cancer Research (2005)

Abstract 8-Oxoguanine is one of the oxidative DNA damages that can result in stable mutations. The Ogg1 gene encodes the repair enzyme 8-oxoguanine-DNA glycosylase, which removes the oxidized base from DNA. In this study, we investigated the role of 8-oxoguanine in skin carcinogenesis induced by UVB irradiation using Ogg1 knockout mice (C57Bl/6J background). We examined the effect of UVB irradiation on the formation of 8-oxoguanine in epidermal cells using immunostaining and found that the level of 8-oxoguanine in Ogg1 knockout mice 24 hours after UVB irradiation remained high compared with that in wild-type and heterozygous mice. To verify the effect of chronic UVB irradiation on 8-oxoguanine formations in epidermal cells, we irradiated wild-type, heterozygous, and Ogg1 knockout mice with UVB at a dose of 2.5 kJ/m2 thrice a week for 40 weeks. We found that the mean number of tumors in Ogg1 knockout mice was 3.71, which was significantly more than in wild-type and heterozygous mice, being 1.71 and 2.28, respectively. The rate of developing malignant tumors in Ogg1 knockout mice was also significantly higher (88.5%; squamous cell carcinomas, 73.1%; sarcomas, 15.4%) than in wild-type mice (50.0%; squamous cell carcinomas, 41.7%; sarcomas, 8.3%). Moreover, the age of onset of developing skin tumors in Ogg1 knockout mice was earlier than in the other types of mice. These results clearly indicate that oxidative DNA damage induced by sunlight plays an important role in the development of skin cancers.